Catalytic Deuteration of Aldehydes with D 2 O

Article abstract of DOI:10.1055/s-0036-1588540

A procedure is presented that enables the direct deuteration of the formyl C-H bond of aldehydes using D ₂ O as the deuterium source and commercially available RuHCl(CO)(PPh ₃) ₃ as the catalyst. Up to 84% deuterium incorp

Full text of DOI:10.1055/s-0036-1588540

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
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A
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E. S. Isbrandt et al.
Letter
Synlett
Catalytic Deuteration of Aldehydes with D2O
Eric S. Isbrandt
O
O
RuHCl(CO)(PPh3)3 (5 mol%)
D2O (5 equiv)
R
R
Jaya Kishore Vandavasi
H
D
Wanying Zhang
PhMe, 100 °C, 30 min
Mohammad P. Jamshidi
Stephen G. Newman*
Direct labeling
Abundant deuterium source
Up to 84% deuteration
Inexpensive catalyst
Centre for Catalysis Research and Innovation, Department of
Chemistry and Biomolecular Sciences, University of Ottawa,
10 Marie Curie, Ottawa, Ontario, K1N 6N5, Canada
stephen.newman@uottawa.ca
Dedicated to Professor Victor Snieckus on the occasion of his
80th birthday
Received: 19.06.2017
Accepted after revision: 17.07.2017
Published online: 21.08.2017
A) Strategies for preparing formyl-deuterated aldehydes
O
1. LiAlD4
2. [O]
O
Pd, D2
DOI: 10.1055/s-0036-1588540; Art ID: st-2017-r0495-l
R
OR'
R
Cl
O
Abstract A procedure is presented that enables the direct deuteration
of the formyl C–H bond of aldehydes using D2O as the deuterium
source and commercially available RuHCl(CO)(PPh3)3 as the catalyst. Up
to 84% deuterium incorporation can be achieved in a single experiment.
Multiple iterations can be carried out to further increase the deutera-
tion.
R
D
1. BuLi; then, D2O
2. HgCl2
O
Cp2ZrDCl
S
R
S
H
R
NR'2
B) Strategies for direct, catalytic deuterations with D2O
Key words aldehydes, isotopic labeling, ruthenium, deuteration, H/D
H
D
exchange
R
R
RuHCl(CO)(PPh3)3 (3 mol%)
D2O, 100 °C
H
D
H
D
Deuterated molecules have a range of practical applica-
tions including use as pharmaceuticals and tools for prob-
ing reaction mechanisms and metabolic pathways.1 Many
strategies have been developed for accessing deuterated
molecules; however, most require multiple chemical steps
and/or use expensive deuterated reagents. For the prepara-
tion of formyl-deuterated aldehydes, reduction of the corre-
sponding ester with lithium aluminum deuteride and sub-
sequent oxidation is most common (Scheme 1, A).2 Other
methods include treatment of amides with Cp2ZrDCl,3
Rosenmund reduction of acid chlorides with D2 gas,4 and
H/D exchange of dithianes.5 The ideal method for preparing
deuterated aldehydes would be to treat the parent aldehyde
directly with an inexpensive deuterating agent.6 Unfortu-
nately, such strategies are rare.7,8
H
H
H
D D
Ru-MACHO (0.2 mol%)
KOtBu (0.5 mol%)
R
R
R
R
H
D
O
O
D2O, 60 °C
[RuCl2(p-cymene)]2 (1.5 mol%)
ethanolamine (3 mol%)
KOH (15 mol%)
H
D D
OH
OD
D2O, 80 °C
C) This work
O
O
RuHCl(CO)(PPh3)3 (5 mol%)
D2O (5 equiv)
R
R
H
D
PhMe, 100 °C
Over the past decade, a growing number of methods has
been developed for directly deuterating molecules using
readily available catalysts and D2O as an abundant, inex-
pensive deuterium source (Scheme 1, B). For example, di-
rect H/D exchange of olefins has been achieved by direct
treatment with a ruthenium catalyst and D2O as both sol-
vent and deuterium source.9 Alcohols have been selectively
Scheme 1 Strategies for synthesizing deuterium-labeled molecules
deuterated at the α- or α,β-positions using the commercial-
ly available ruthenium hydride catalyst Ru-MACHO.10 The
alcohol β-position can also be deuterated while maintain-
ing protium in the α-position using a ruthenium(II)–etha-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
E. S. Isbrandt et al.
Letter
Synlett
nolamine catalyst system.11 Reactions within this family are
generally proposed to occur by a series of H/D exchange, li-
gand substitution, insertion, and deinsertion reactions of
the metal catalyst. Given the challenges associated with the
synthesis of formyl-deuterated aldehydes, we sought to ex-
plore a similar strategy using aldehydes rather than olefins
or alcohols as substrates. Herein, we present how good
yields and modest to good formyl-selective deuterium in-
corporation can be achieved directly from the parent alde-
hyde (Scheme 1, C).
The transformation of 2-naphthaldehyde (1a) into its
formyl-deuterated analogue 2a was chosen for reaction de-
velopment. RuHCl(CO)(PPh3)3 was selected as the catalyst
due to its ease of synthesis from inexpensive RuCl3.12 Pre-
liminary studies with structurally related RuH2(CO)(PPh3)3,
RuHCl(PPh3)3, and RuHCl(CO)(PCy3)3 showed them to be
less effective than RuHCl(CO)(PPh3). The optimal conditions
identified used 5 mol% catalyst and five equivalents of D2O
in toluene (0.2 M), stirring for 30 minutes at 100 °C
(Table 1). With these conditions, 72% deuterium incorpora-
tion of 2-naphthaldehyde was obtained (Table 1, entry 1).
Counterintuitively, the use of more equivalents of D2O led
to a decrease in deuterium incorporation (Table 1, entries
2–4).
The use of alternative ruthenium catalysts (Table 1, en-
tries 5–7) or the addition of ligands (Table 1, entries 8, 9)
was not beneficial; however, catalyst loadings can have a
significant influence on the reaction (Table 1, entries 10,
11). Carboxylic acids are common impurities in aldehydes.
In order to test its effects, a reaction was spiked with 0.05
equivalents of benzoic acid, which completely inhibited the
reaction (Table 1, entry 12). Unfortunately, basic additives
such as K2CO3 (Table 1, entry 13) and Et3N (Table 1, entry
14) also inhibited the reaction, so the use of pure starting
material is critical for obtaining high levels of deuteration.
Finally, the reaction was performed in an open vessel with
no attempts made to exclude moisture and oxygen, in
which only minor loss in deuterium incorporation was ob-
served (Table 1, entry 15). In contrast to other known meth-
ods,13 no notable deuterium incorporation into the aromat-
ic ring was observed in any of the above reactions. The abil-
ity to selectively deuterate the formyl position of the
aldehyde is advantageous and offers a distinct advantage
compared to similar transformations reported in the prima-
ry literature.8
The robustness and generality of the transformation
was then evaluated (Scheme 2).14 Deuterated naphthalde-
hyde 2a was isolated in 89% yield after purification by col-
umn chromatography, indicating that minimal decomposi-
tion and side-product formation occurs. A range of substi-
tuted electron-neutral and electron-rich aryl aldehyde
derivatives gave between 50% and 84% deuterium incorpo-
ration (2b–g). Heterocyclic indole (2h) and pyrrole (2i) al-
dehydes were also prepared, albeit with modest deuterium
incorporation. The reaction was tolerant of unprotected
phenolic groups in the ortho (2j) or para (2k) positions. In
contrast, electron-poor substrates such as methyl 4-formyl-
benzoate (2l) provided poor deuterium incorporation. Ali-
phatic aldehydes proved similarly challenging, primarily
due to the formation of side-products that prohibited
straightforward isolation and analysis.
Table 1 Optimization of the Catalytic Formyl-Deuteration Reaction
O
O
RuHCl(CO)(PPh3)3 (5 mol%)
D2O (5 equiv)
H
D
PhMe, 100 °C, 0.5 h
2a
1a
Entry
Deviation from optimal reaction conditions
Deuteration (%)a
1
2
none
72
10 equiv D2O
41
3
20 equiv D2O
52
4
D2O as solvent
18
Many applications of deuterated molecules require
highly pure compounds with very high deuterium incorpo-
ration. To determine the viability of the process for these
instances, an iterative process was explored. Starting from
0.3 mmol of naphthaldehyde (1a), three sequential reac-
tions and rapid purifications were carried out (Scheme 3).
The first iteration provided 0.27 mmol of 2a (90% yield)
with 73% deuterium incorporation. Resubjection of the ma-
terial to the reaction conditions and further purification for
a second and third iteration ultimately provided 0.20 mmol
of 2a with 96% deuterium incorporation.
While thorough evaluation is required to get a detailed
understanding of reaction mechanism, a reasonable pro-
posal can be made from precedent literature. It has been
shown in stoichiometric experiments that ruthenium hy-
drides can exchange with D2O to form ruthenium deu-
terides and HDO.9 Furthermore, the insertion and elimina-
5
RuH2(CO)(PPh3)3 as catalyst
Ru3(CO)12as catalyst
21
6
trace
trace
trace
68
7
Ru-MACHO
8
dppf (5 mol%) as an additive
BINAP (5 mol%) as an additive
3 mol% catalyst loading
10 mol% catalyst loading
0.05 equiv PhCO2H as an additive
1 equiv K2CO3 as an additive
1 equiv Et3N as an additive
no exclusion of air and moisture
9
10
11
12
13
14
15
64
85
trace
30
47
68
a Deuterium incorporation determined by integration of the residual formyl
proton in 1H NMR.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
E. S. Isbrandt et al.
Letter
Synlett
tion of these steps (Scheme 4). Exchange of the hydride
with a deuterium from D2O can occur to provide a rutheni-
um deuteride intermediate. Coordination and insertion of
the aldehyde would give a ruthenium alkoxide bearing one
deuterium and one protium on the alkoxide α-carbon. Sub-
sequent β-hydride elimination would provide the formyl-
deuterated aldehyde product and regenerate the initial ru-
thenium hydride. Given the near thermoneutral nature of
the transformation, each step is likely in equilibrium. As a
consequence, a reasonable maximum deuterium incorpora-
tion of 91% can be expected when using five equivalents of
D2O. The more modest deuterium incorporation in the reac-
tion, as well as the decrease in deuteration when using
larger quantities of D2O (Table 1, entries 1–3), suggest that
the activity and potential deactivation of the catalyst also
plays a significant role in the reaction outcome, and further
catalyst development may lead to further improvements.
RuHCl(CO)(PPh3)3 (5 mol%)
O
O
D2O (5 equiv)
R
H
R
D
PhMe, 100 °C, 0.5 h
O
O
O
D
D
D
MeO
2a, 89% yield
72% deuteration
2b, 76% yield
84% deuteration
2c, 90% yield
84% deuteration
O
O
O
MeO
D
D
D
MeO
MeS
2d, 81%, yield
84% deuteration
2e, 79% yield
63% deuteration
2f, 92% yield
74% deuteration
O
D
O
D
O
O
N
D
D2O
[Ru]
H
N
R
D
R
Boc
HDO
2g, 68% yielda
55% deuteration
2h, 89% yield
44% deuteration
2i, 65% yield
51% deuteration
[Ru]
O
[Ru]
R
D
D
OH
O
H
O
O
O
D
D
D
H
O
Scheme 4 A plausible reaction mechanism
HO
OMe
2j, 92% yield
75% deuteration
2k, 95% yield
80% deuteration
2l, 60% yield
14% deuteration
In conclusion, a new method for the direct deuteration
of the formyl C–H bond of aldehydes has been developed.
The reaction uses an inexpensive, abundant ruthenium cat-
alyst to facilitate the reaction with five equivalents of D2O
as the deuterium source. Moderate to good deuterium in-
corporation can be achieved in the 30 minute reaction time,
provided that pure aldehydes with minimal carboxylic acid
impurities are used. Excellent deuterium incorporation can
be achieved if the product is resubjected to the reaction
conditions. While more limited in scope than classical stoi-
chiometric methods for generating deuterated aldehydes,
and acknowledging the effectiveness of the recently pub-
lished iridium-catalyzed systems,8 the current approach is
remarkably simple, inexpensive, and direct, making it a po-
tentially appealing additional method for application in this
general area.
Scheme 2 Scope of aldehyde H/D exchange in D2O. Reagents and con-
ditions: Aldehyde (0.3 mmol), RuHCl(CO)(PPh3)3 (0.015 mmol), D2O
(1.5 mmol), and toluene (1.5 mL) were heated in a sealed vial for 30
min. Deuterium incorporation was determined by integration of the 1H
NMR spectra of both the crude and purified products. ‘Yield’ refers to
the amount of both the H- and D-containing product obtained after
purification. a Yield determined by crude 1H NMR analysis due to volatil-
ity of the product.
O
O
RuHCl(CO)(PPh3)3 (5 mol%)
D2O (5 equiv)
H
D
PhMe, 100 °C, 0.5 h
1a
2a
0.3 mmol
Iteration 1 0.27 mmol, 73% D
Purify & resubject
to reaction
Iteration 2 0.24 mmol, 92% D
Purify & resubject
to reaction
Funding Information
Iteration 3 0.20 mmol, 96% D
Financial support for this work was provided by the University of Ot-
tawa, the National Science and Engineering Research Council of Cana-
da (NSERC), and the Canada Research Chair program. The Canadian
Foundation for Innovation (CFI) and the Ontario Ministry of Economic
Development and Innovation are thanked for essential infrastructure.
E.I. thanks NSERC and the Government of Ontario for USRA and OGS
Scheme 3 Iterative deuteration experiments enable access to increas-
ingly deuterium-enriched material
tion of carbonyls into ruthenium hydride bonds is a well-
established step in transfer hydrogenation and related reac-
tions.15 A plausible mechanism would, thus, be a combina-
scholarships, respectively.
)(
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
E. S. Isbrandt et al.
Letter
Synlett
Supporting Information
(7) Defoin, A.; Defoin-Straathann, R.; Kuhn, H. J. Tetrahedron 1984,
14, 2651.
(8) During the completion of this manuscript, an Ir-catalyzed
method to deuterate aldehydes using D2 gas was published. See:
Kerr, W. J.; Reid, M.; Tuttle, T. Angew. Chem. Int. Ed. 2017, 129,
7916.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588540.
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ortioInfgrmoaitn
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ortiInfogrmoaitn
References and Notes
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(14) Representative Procedure for Aldehyde Deuteration
2-Naphthaldehyde (1a, 46.9 mg, 0.3 mmol) and RuHCl(CO)(PPh3)3
(14.3 mg, 0.015 mmol, 5 mol%) were dissolved in PhMe (1.5 mL,
0.2 M) in an oven-dried screw-cap vial. D2O (27 μL, 1.5 mmol)
was then added. The vial was sparged with argon and capped.
The resulting solution was heated to 100 °C and stirred for 30
min. At the end of the reaction, the solvent was removed in
vacuo and the crude material was purified by column chroma-
tography using a 2 → 8% EtOAc in hexane gradient to afford 41.9
mg 2a as a white solid (89% yield, 72% D). 1H NMR (400 MHz,
CDCl3): δ = 8.35 (s, 1 H), 8.02–7.90 (m, 4 H), 7.67–7.57 (m, 2 H).
Residual formyl proton: δ = 10.1.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D